Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system (CNS) and is characterized by the presence of demyelinated areas throughout the CNS. Various mechanisms leading to demyelination and axonal suffering have been implicated and the production of toxic inflammatory mediators by infiltrating and resident CNS macrophages is believed to play a pivotal role. MS is thought to be caused by a combined cellular and humoral autoimmune attack on myelin sheaths and possibly axons. Several facts have contributed to the concept that MS is an autoimmune disease, such as the association with various regulatory genes of the immune response, the presence of oligoclonal immunoglobulin species in CSF pointing to intrathecal expansion of specific B-cell clones, and the immunopathology of the lesions. Further support comes from the immunopathological similarity of MS with the autoimmune animal model EAE (experimental autoimmune/allergic encephalomyelitis) in rodents and primates, which, considering that no in vitro models exist is the only experimental model existing so far that may be used to test scientific hypotheses on the critical pathogenetic mechanisms and for the development of more effective therapies. However, the substantial dissimilarities between MS and EAE models have among others raised doubts about the autoimmune origin of MS. Notably, many of the EAE models present as a rapidly progressing monophasic disease with clinical and pathological findings that are more reminiscent of acute disseminated encephalomyelitis than chronic and relapsing MS. Although exceptions do exist, such as the elegant EAE model in Biozzi/ABH mice immunized with spinal-cord homogenate and a non-human-primate model for chronic MS in common marmosets that approximate the human disease better, currently no existing experimental model bridges the considerable gap between EAE models and MS.
Different subsets of myeloid cells are considered to have distinct roles in the development of MS. These distinct and specialized roles of myeloid cells depend on their origin and, importantly, their location. As such, perivascular cells appear to be optimally positioned for the modulation of infiltrating T cell activity whereas parenchymal myeloid cells may have a more prominent role in mechanisms involved in myelin breakdown and axonal suffering.
The plasticity and functional polarization of macrophages have received renewed attention in light of novel key properties of different forms of macrophages. Two extremes of a continuum have been identified for macrophages, being M1, or classically activated macrophages, and M2, or alternatively activated macrophages. The M1 phenotype is typically induced in vitro by IFN-gamma, TNF-alpha or LPS, whereas the M2 phenotype can be induced by IL-10, IL-4 or by the lipid mediator PGE2, which is a strong inhibitor of pro-inflammatory immune responses. M1 macrophages are characterized by a high production of pro-inflammatory mediators and are involved in Th1 cell responses and killing of micro-organisms and tumor cells. In contrast, M2 macrophages are associated with Th2 responses, scavenging of debris, promotion of tissue remodeling and repair and expression of anti-inflammatory molecules, including IL-1ra (IL-1 receptor antagonist) and CCL18. CCL18 in particular is a specific marker for human alternatively activated macrophages and is involved in immune suppression.
Demyelinating MS lesions are characterized by the presence of foamy macrophages, a characteristic subset of myeloid cells, which acquire their distinctive morphology by ingestion and accumulation of vast amounts of myelin-derived lipids. Foamy macrophages originate from both resident microglia and infiltrating monocytes, and about 30-80% of foamy macrophages in demyelinating lesions are blood-derived. Besides their apparent role in scavenging myelin, it is still poorly understood if and how foamy macrophages may affect the local inflammatory process. Since MS lesions are self-limiting and do not expand indefinitely it is likely that local mechanisms restrict CNS inflammation and may also promote tissue repair. It is however up to now not clear how these local mechanisms may function.